Acta Neuropathologica

, Volume 128, Issue 3, pp 319–331 | Cite as

Microglia: unique and common features with other tissue macrophages

  • Marco PrinzEmail author
  • Tuan Leng Tay
  • Yochai Wolf
  • Steffen JungEmail author


Microglia are highly specialized tissue macrophages of the brain with dedicated functions in neuronal development, homeostasis and recovery from pathology Despite their unique localization in the central nervous system (CNS), microglia are ontogenetically and functionally related to their peripheral counterparts of the mononuclear phagocytic system in the body, namely tissue macrophages and circulating myeloid cells. Recent developments provided new insights into the myeloid system in the body with microglia emerging as intriguing unique archetypes. Similar to other tissue macrophages, microglia develop early during embryogenesis from immature yolk sac progenitors. But in contrast to most of their tissue relatives microglia persist throughout the entire life of the organism without any significant input from circulating blood cells due to their longevity and their capacity of self-renewal. Notably, microglia share some features with short-lived blood monocytes to limit CNS tissue damage in pathologies, but only bone marrow-derived cells display the ability to become permanently integrated in the parenchyma. This emphasizes the therapeutic potential of bone marrow-derived microglia-like cells. Further understanding of both fate and function of microglia during CNS pathologies and considering their uniqueness among other tissue macrophages will be pivotal for potential manipulation of immune cell function in the CNS, thereby reducing disease burden. Here, we discuss new aspects of myeloid cell biology in general with special emphasis on the brain-resident macrophages and microglia.


Microglia Yolk sac Bone marrow Inflammation Monocytes Neurodegeneration CX3CR1 CX3CR1Cre 



This work was supported by the DFG funded research unit (FOR) 1336 (to MP & SJ), the BMBF-funded Competence Network of Multiple Sclerosis (KKNMS to MP), the Competence Network of Neurodegenerative Disorders (KNDD to MP), the Centre of Chronic Immunodeficiency (CCI to MP), and the DFG (PR 577/8-2 to MP and TA1029/1-1 to TLT).


  1. 1.
    Abutbul S, Shapiro J, Szaingurten-Solodkin I et al (2012) TGF-β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia 60:1160–1171. doi: 10.1002/glia.22343 PubMedGoogle Scholar
  2. 2.
    Ajami B, Bennett JL, Krieger C et al (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543. doi: 10.1038/nn2014 PubMedGoogle Scholar
  3. 3.
    Ajami B, Bennett JL, Krieger C et al (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149. doi: 10.1038/nn.2887 PubMedGoogle Scholar
  4. 4.
    Ang S-L (2006) Transcriptional control of midbrain dopaminergic neuron development. Development 133:3499–3506. doi: 10.1242/dev.02501 PubMedGoogle Scholar
  5. 5.
    Auffray C, Fogg D, Garfa M et al (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317:666–670. doi: 10.1126/science.1142883 PubMedGoogle Scholar
  6. 6.
    Bauer S, Kerr BJ, Patterson PH (2007) The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 8:221–232PubMedGoogle Scholar
  7. 7.
    Bechmann I, Priller J, Kovac A et al (2001) Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14:1651–1658PubMedGoogle Scholar
  8. 8.
    Beers DR, Henkel JS, Xiao Q et al (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. PNAS 103:16021–16026. doi: 10.1073/pnas.0607423103 PubMedCentralPubMedGoogle Scholar
  9. 9.
    Bialas AR, Stevens B (2013) TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 16:1–12. doi: 10.1038/nn.3560 Google Scholar
  10. 10.
    Biber K, Neumann H, Inoue K, Boddeke H (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30:596–602PubMedGoogle Scholar
  11. 11.
    Butovsky O, Siddiqui S, Gabriely G et al (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063–3087. doi: 10.1172/JCI62636 PubMedCentralPubMedGoogle Scholar
  12. 12.
    Butovsky O, Jedrychowski MP, Moore CS et al (2013) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143. doi: 10.1038/nn.3599 PubMedCentralPubMedGoogle Scholar
  13. 13.
    Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924. doi: 10.1038/nn1715 PubMedGoogle Scholar
  14. 14.
    Cartier N, Hacein-Bey-Abina S, Bartholomae CC et al (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818–823. doi: 10.1126/science.1171242 PubMedGoogle Scholar
  15. 15.
    Celada A, Borràs FE, Soler C et al (1996) The transcription factor PU.1 is involved in macrophage proliferation. J Exp Med 184:61–69PubMedGoogle Scholar
  16. 16.
    Chen S-K, Tvrdik P, Peden E et al (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141:775–785. doi: 10.1016/j.cell.2010.03.055 PubMedCentralPubMedGoogle Scholar
  17. 17.
    Choi SH, Veeraraghavalu K, Lazarov O et al (2008) Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron 59:568–580. doi: 10.1016/j.neuron.2008.07.033 PubMedCentralPubMedGoogle Scholar
  18. 18.
    Coull JAM, Beggs S, Boudreau D et al (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021. doi: 10.1038/nature04223 PubMedGoogle Scholar
  19. 19.
    Dantzer R, O’Connor JC, Freund GG et al (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56. doi: 10.1038/nrn2297 PubMedCentralPubMedGoogle Scholar
  20. 20.
    Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758. doi: 10.1038/nn1472 PubMedGoogle Scholar
  21. 21.
    Davies LC, Rosas M, Smith PJ et al (2011) A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. Eur J Immunol 41:2155–2164. doi: 10.1002/eji.201141817 PubMedGoogle Scholar
  22. 22.
    Davies LC, Rosas M, Jenkins SJ et al (2013) Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun 4:1886. doi: 10.1038/ncomms2877 PubMedGoogle Scholar
  23. 23.
    Derecki NC, Cronk JC, Lu Z et al (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484:105–109. doi: 10.1038/nature10907 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Djukic M, Mildner A, Schmidt H et al (2006) Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129:2394–2403. doi: 10.1093/brain/awl206 PubMedGoogle Scholar
  25. 25.
    Dumser M, Bauer J, Lassmann H et al (2007) Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency. Acta Neuropathol 114:573–586. doi: 10.1007/s00401-007-0288-4 PubMedGoogle Scholar
  26. 26.
    Ekdahl CT, Claasen J-H, Bonde S et al (2003) Inflammation is detrimental for neurogenesis in adult brain. PNAS 100:13632–13637. doi: 10.1073/pnas.2234031100 PubMedCentralPubMedGoogle Scholar
  27. 27.
    Epelman S, Lavine KJ, Beaudin AE et al (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91–104. doi: 10.1016/j.immuni.2013.11.019 PubMedGoogle Scholar
  28. 28.
    Erblich B, Zhu L, Etgen AM et al (2011) Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One 6:e26317. doi: 10.1371/journal.pone.0026317.t002 PubMedCentralPubMedGoogle Scholar
  29. 29.
    Fenoglio C, Galimberti D, Piccio L et al (2007) Absence of TREM2 polymorphisms in patients with Alzheimer’s disease and Frontotemporal Lobar Degeneration. Neurosci Lett 411:133–137. doi: 10.1016/j.neulet.2006.10.029 PubMedGoogle Scholar
  30. 30.
    van Furth R, Cohn ZA (1968) The origin and kinetics of mononuclear phagocytes. J Exp Med 128:415–435PubMedCentralPubMedGoogle Scholar
  31. 31.
    Gadani SP, Cronk JC, Norris GT, Kipnis J (2012) IL-4 in the brain: a cytokine to remember. J Immunol 189:4213–4219. doi: 10.4049/jimmunol.1202246 PubMedCentralPubMedGoogle Scholar
  32. 32.
    Gautier EL, Shay T, Miller J et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13:1118–1128. doi: 10.1038/ni.2419 PubMedCentralPubMedGoogle Scholar
  33. 33.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82PubMedGoogle Scholar
  34. 34.
    Gemma C, Bachstetter AD (2013) The role of microglia in adult hippocampal neurogenesis. Front Cell Neurosci 7:229. doi: 10.3389/fncel.2013.00229 PubMedCentralPubMedGoogle Scholar
  35. 35.
    Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845. doi: 10.1126/science.1194637 PubMedCentralPubMedGoogle Scholar
  36. 36.
    Gitik M, Liraz-Zaltsman S, Oldenborg P-A et al (2011) Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes. J Neuroinflammation 8:24. doi: 10.1186/1742-2094-8-24 PubMedCentralPubMedGoogle Scholar
  37. 37.
    Goldmann T, Prinz M (2013) Role of microglia in CNS autoimmunity. Clin Dev Immunol 2013:208093. doi: 10.1155/2013/208093 PubMedCentralPubMedGoogle Scholar
  38. 38.
    Goldmann T, Tay TL, Prinz M (2013) Love and death: microglia, NLRP3 and the Alzheimer’s brain. Cell Res 23(5):1–2. doi: 10.1038/cr.2013.24 Google Scholar
  39. 39.
    Goldmann T, Wieghofer P, Müller PF et al (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16:1618–1626. doi: 10.1038/nn.3531 PubMedGoogle Scholar
  40. 40.
    Gomez-Nicola D, Fransen NL, Suzzi S, Perry VH (2013) Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci 33:2481–2493. doi: 10.1523/JNEUROSCI.4440-12.2013 PubMedGoogle Scholar
  41. 41.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964. doi: 10.1038/nri1733 PubMedGoogle Scholar
  42. 42.
    Guedes J, Cardoso ALC, Pedroso de Lima MC (2013) Involvement of microRNA in microglia-mediated immune response. Clin Dev Immunol 2013:186872. doi: 10.1155/2013/186872 PubMedCentralPubMedGoogle Scholar
  43. 43.
    Guilliams M, De Kleer I, Henri S et al (2013) Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med 210:1977–1992. doi: 10.1084/jem.20131199 PubMedCentralPubMedGoogle Scholar
  44. 44.
    Hambleton S, Salem S, Bustamante J et al (2011) IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med 365:127–138. doi: 10.1056/NEJMoa1100066 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Hamerman JA, Jarjoura JR, Humphrey MB et al (2006) Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 177:2051–2055PubMedGoogle Scholar
  46. 46.
    Hanisch U-K, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394. doi: 10.1038/nn1997 PubMedGoogle Scholar
  47. 47.
    Hashimoto D, Chow A, Noizat C et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792–804. doi: 10.1016/j.immuni.2013.04.004 PubMedGoogle Scholar
  48. 48.
    Heneka MT, Kummer MP, Stutz A et al (2012) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. doi: 10.1038/nature11729 PubMedGoogle Scholar
  49. 49.
    Herbomel P, Thisse B, Thisse C (1999) Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126:3735–3745PubMedGoogle Scholar
  50. 50.
    Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292PubMedGoogle Scholar
  51. 51.
    Hickman SE, Kingery ND, Ohsumi TK et al (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–1905. doi: 10.1038/nn.3554 PubMedGoogle Scholar
  52. 52.
    Hoeffel G, Wang Y, Greter M et al (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209:1167–1181. doi: 10.1084/jem.20120340 PubMedCentralPubMedGoogle Scholar
  53. 53.
    Hoek RM, Ruuls SR, Murphy CA et al (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771. doi: 10.1126/science.290.5497.1768 PubMedGoogle Scholar
  54. 54.
    Hoshiko M, Arnoux I, Avignone E et al (2012) Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci 32:15106–15111. doi: 10.1523/JNEUROSCI.1167-12.2012 PubMedGoogle Scholar
  55. 55.
    Jovicic A, Roshan R, Moisoi N et al (2013) Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes. J Neurosci 33:5127–5137. doi: 10.1523/JNEUROSCI.0600-12.2013 PubMedGoogle Scholar
  56. 56.
    Jung S, Aliberti J, Graemmel P et al (2000) Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114. doi: 10.1128/MCB.20.11.4106-4114.2000 PubMedCentralPubMedGoogle Scholar
  57. 57.
    Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553. doi: 10.1152/physrev.00011.2010 PubMedGoogle Scholar
  58. 58.
    Kierdorf K, Erny D, Goldmann T et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16:273–280. doi: 10.1038/nn.3318 PubMedGoogle Scholar
  59. 59.
    Kierdorf K, Katzmarski N, Haas CA, Prinz M (2013) Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS One 8:e58544. doi: 10.1371/journal.pone.0058544.s001 PubMedCentralPubMedGoogle Scholar
  60. 60.
    Kierdorf K, Prinz M (2013) Factors regulating microglia activation. Front Cell Neurosci. doi: 10.3389/fncel.2013.00044/abstract PubMedCentralPubMedGoogle Scholar
  61. 61.
    Kim K-W, Vallon-Eberhard A, Zigmond E et al (2011) In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 118:e156–e167. doi: 10.1182/blood-2011-04-348946 PubMedGoogle Scholar
  62. 62.
    Klünemann HH, Ridha BH, Magy L et al (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502–1507. doi: 10.1212/01.WNL.0000160304.00003.CA PubMedGoogle Scholar
  63. 63.
    Kurz H, Christ B (1998) Embryonic CNS macrophages and microglia do not stem from circulating, but from extravascular precursors. Glia 22:98–102PubMedGoogle Scholar
  64. 64.
    Lagasse E, Weissman IL (1996) Flow cytometric identification of murine neutrophils and monocytes. J Immunol Methods 197:139–150PubMedGoogle Scholar
  65. 65.
    Lambertsen KL, Deierborg T, Gregersen R et al (2011) Differences in origin of reactive microglia in bone marrow chimeric mouse and rat after transient global ischemia. J Neuropathol Exp Neurol 70:481–494. doi: 10.1097/NEN.0b013e31821db3aa PubMedGoogle Scholar
  66. 66.
    Lampron A, Pimentel-Coelho PM, Rivest S (2013) Migration of bone marrow-derived cells into the central nervous system in models of neurodegeneration. J Comp Neurol 521:3863–3876. doi: 10.1002/cne.23363 PubMedGoogle Scholar
  67. 67.
    Lavin Y, Merad M (2013) Macrophages: gatekeepers of tissue integrity. Cancer Immunol Res 1:201–209. doi: 10.1158/2326-6066.CIR-13-0117 PubMedGoogle Scholar
  68. 68.
    Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405–415PubMedGoogle Scholar
  69. 69.
    Le W-D, Xu P, Jankovic J et al (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89. doi: 10.1038/ng1066 PubMedGoogle Scholar
  70. 70.
    Liddiard K, Rosas M, Davies LC et al (2011) Macrophage heterogeneity and acute inflammation. Eur J Immunol 41:2503–2508. doi: 10.1002/eji.201141743 PubMedGoogle Scholar
  71. 71.
    Lin H, Lee E, Hestir K et al (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320:807–811. doi: 10.1126/science.1154370 PubMedGoogle Scholar
  72. 72.
    Liu Y, Teige I, Birnir B, Issazadeh-Navikas S (2006) Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat Med 12:518–525. doi: 10.1038/nm1402 PubMedGoogle Scholar
  73. 73.
    Marín-Teva JL, Dusart I, Colin C et al (2004) Microglia promote the death of developing Purkinje cells. Neuron 41:535–547PubMedGoogle Scholar
  74. 74.
    Massengale M, Wagers AJ, Vogel H, Weissman IL (2005) Hematopoietic cells maintain hematopoietic fates upon entering the brain. J Exp Med 201:1579–1589. doi: 10.1084/jem.20050030 PubMedCentralPubMedGoogle Scholar
  75. 75.
    Masuda T, Tsuda M, Yoshinaga R et al (2012) IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep 1:334–340. doi: 10.1016/j.celrep.2012.02.014 PubMedGoogle Scholar
  76. 76.
    Matsumoto Y, Fujiwara M (1987) Absence of donor-type major histocompatibility complex class I antigen-bearing microglia in the rat central nervous system of radiation bone marrow chimeras. J Neuroimmunol 17:71–82PubMedGoogle Scholar
  77. 77.
    McKercher SR, Torbett BE, Anderson KL et al (1996) Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15:5647–5658PubMedCentralPubMedGoogle Scholar
  78. 78.
    Michaelson MD, Bieri PL, Mehler MF et al (1996) CSF-1 deficiency in mice results in abnormal brain development. Development 122:2661–2672PubMedGoogle Scholar
  79. 79.
    Mildner A, Schmidt H, Nitsche M et al (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553. doi: 10.1038/nn2015 PubMedGoogle Scholar
  80. 80.
    Mildner A, Djukic M, Garbe D et al (2008) Ly-6G + CCR2- myeloid cells rather than Ly-6ChighCCR2+ monocytes are required for the control of bacterial infection in the central nervous system. J Immunol 181:2713–2722PubMedGoogle Scholar
  81. 81.
    Mildner A, Mack M, Schmidt H et al (2009) CCR2+ Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132:2487–2500. doi: 10.1093/brain/awp144 PubMedGoogle Scholar
  82. 82.
    Mildner A, Schlevogt B, Kierdorf K et al (2011) Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci 31:11159–11171. doi: 10.1523/JNEUROSCI.6209-10.2011 PubMedGoogle Scholar
  83. 83.
    Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10:850–860. doi: 10.1038/nrn2738 PubMedGoogle Scholar
  84. 84.
    Minten C, Terry R, Deffrasnes C et al (2012) IFN Regulatory Factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS. PLoS One 7:e49851. doi: 10.1371/journal.pone.0049851.g006 PubMedCentralPubMedGoogle Scholar
  85. 85.
    Mizrahi A (2007) Dendritic development and plasticity of adult-born neurons in the mouse olfactory bulb. Nat Neurosci 10:444–452. doi: 10.1038/nn1875 PubMedGoogle Scholar
  86. 86.
    Mizutani M, Pino PA, Saederup N et al (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol 188:29–36. doi: 10.4049/jimmunol.1100421 PubMedCentralPubMedGoogle Scholar
  87. 87.
    Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765. doi: 10.1126/science.1088417 PubMedGoogle Scholar
  88. 88.
    Moran LB, Graeber MB (2004) The facial nerve axotomy model. Brain Res Brain Res Rev 44:154–178PubMedGoogle Scholar
  89. 89.
    Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737. doi: 10.1038/nri3073 PubMedCentralPubMedGoogle Scholar
  90. 90.
    Nandi S, Gokhan S, Dai X-M et al (2012) The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev Biol 367:100–113. doi: 10.1016/j.ydbio.2012.03.026 PubMedCentralPubMedGoogle Scholar
  91. 91.
    Neumann H, Daly MJ (2013) Variant TREM2 as risk factor for Alzheimer’s disease. N Engl J Med 368:182–184. doi: 10.1056/NEJMe1213157 PubMedGoogle Scholar
  92. 92.
    Neumann H, Wekerle H (2013) Brain microglia: watchdogs with pedigree. Nat Neurosci 16:253–255. doi: 10.1038/nn.3338 PubMedGoogle Scholar
  93. 93.
    Nimmerjahn A (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. doi: 10.1126/science.1110647 PubMedGoogle Scholar
  94. 94.
    Numasawa Y, Yamaura C, Ishihara S et al (2010) Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family. Eur J Neurol 18:1179–1183. doi: 10.1111/j.1468-1331.2010.03311.x PubMedGoogle Scholar
  95. 95.
    Otero K, Turnbull IR, Poliani PL et al (2009) Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat Immunol 10:734–743. doi: 10.1038/ni.1744 PubMedCentralPubMedGoogle Scholar
  96. 96.
    Paloneva J, Kestilä M, Wu J et al (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25:357–361. doi: 10.1038/77153 PubMedGoogle Scholar
  97. 97.
    Paolicelli RC, Bolasco G, Pagani F et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458. doi: 10.1126/science.1202529 PubMedGoogle Scholar
  98. 98.
    Parkhurst CN, Yang G, Ninan I et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609. doi: 10.1016/j.cell.2013.11.030 PubMedCentralPubMedGoogle Scholar
  99. 99.
    Peri F, Nüsslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927. doi: 10.1016/j.cell.2008.04.037 PubMedGoogle Scholar
  100. 100.
    Piccio L, Buonsanti C, Mariani M et al (2007) Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol 37:1290–1301. doi: 10.1002/eji.200636837 PubMedGoogle Scholar
  101. 101.
    Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9:259–270. doi: 10.1038/nri2528 PubMedCentralPubMedGoogle Scholar
  102. 102.
    Ponomarev ED, Veremeyko T, Barteneva N et al (2011) MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med 17:64–70. doi: 10.1038/nm.2266 PubMedCentralPubMedGoogle Scholar
  103. 103.
    Priller J, Flügel A, Wehner T et al (2001) Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7:1356–1361. doi: 10.1038/nm1201-1356 PubMedGoogle Scholar
  104. 104.
    Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14:1227–1235. doi: 10.1038/nn.2923 PubMedGoogle Scholar
  105. 105.
    Radjavi A, Smirnov I, Derecki N, Kipnis J (2013) Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol Psychiatry. doi: 10.1038/mp.2013.79 PubMedGoogle Scholar
  106. 106.
    Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145. doi: 10.1146/annurev.immunol.021908.132528 PubMedGoogle Scholar
  107. 107.
    Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262. doi: 10.1038/nature09615 PubMedGoogle Scholar
  108. 108.
    Rayaprolu S, Mullen B, Baker M et al (2013) TREM2 in neurodegeneration: evidence for association of the p. R47H variant with frontotemporal dementia and Parkinson’s disease. Mol Neurodegener 8:19. doi: 10.1186/1750-1326-8-19 PubMedCentralPubMedGoogle Scholar
  109. 109.
    Robbins CS, Hilgendorf I, Weber GF, Theurl I (2013) Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 19:1166–1172. doi: 10.1038/nm.3258 PubMedCentralPubMedGoogle Scholar
  110. 110.
    Rosenbauer F, Tenen DG (2007) Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 7:105–117. doi: 10.1038/nri2024 PubMedGoogle Scholar
  111. 111.
    Roumier A, Béchade C, Poncer J-C et al (2004) Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 24:11421–11428. doi: 10.1523/JNEUROSCI.2251-04.2004 PubMedGoogle Scholar
  112. 112.
    Saijo K, Winner B, Carson CT et al (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59. doi: 10.1016/j.cell.2009.01.038 PubMedCentralPubMedGoogle Scholar
  113. 113.
    Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787. doi: 10.1038/nri3086 PubMedGoogle Scholar
  114. 114.
    Satoh J-I, Tabunoki H, Ishida T et al (2011) Immunohistochemical characterization of microglia in Nasu–Hakola disease brains. Neuropathology 31:363–375. doi: 10.1111/j.1440-1789.2010.01174.x PubMedGoogle Scholar
  115. 115.
    Schafer DP, Lehrman EK, Kautzman AG et al (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705. doi: 10.1016/j.neuron.2012.03.026 PubMedCentralPubMedGoogle Scholar
  116. 116.
    Schulz C, Perdiguero EG, Chorro L et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90. doi: 10.1126/science.1219179 PubMedGoogle Scholar
  117. 117.
    Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74PubMedGoogle Scholar
  118. 118.
    Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7:311–317. doi: 10.1038/ni1309 PubMedGoogle Scholar
  119. 119.
    Sessa G, Podini P, Mariani M et al (2004) Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci 20:2617–2628. doi: 10.1111/j.1460-9568.2004.03729.x PubMedGoogle Scholar
  120. 120.
    Shechter R, London A, Varol C et al (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6:e1000113. doi: 10.1371/journal.pmed.1000113.s012 PubMedCentralPubMedGoogle Scholar
  121. 121.
    Shechter R, Miller O, Yovel G et al (2013) Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38:555–569. doi: 10.1016/j.immuni.2013.02.012 PubMedCentralPubMedGoogle Scholar
  122. 122.
    Sierra A, Encinas JM, Deudero JJP et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Stem Cell 7:483–495. doi: 10.1016/j.stem.2010.08.014 Google Scholar
  123. 123.
    Simard AR, Soulet D, Gowing G et al (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49:489–502. doi: 10.1016/j.neuron.2006.01.022 PubMedGoogle Scholar
  124. 124.
    Soulas C, Donahue RE, Dunbar CE et al (2009) Genetically modified CD34 + hematopoietic stem cells contribute to turnover of brain perivascular macrophages in long-term repopulated primates. Amer J Pathol 174:1808–1817. doi: 10.2353/ajpath.2009.081010 Google Scholar
  125. 125.
    Stanley ER, Guilbert LJ, Tushinski RJ (1983) CSF-1—a mononuclear phagocyte lineage-specific hemopoietic growth factor. J Cell Biochem 21:151–159PubMedGoogle Scholar
  126. 126.
    Stevens B, Allen NJ, Vazquez LE, Howell GR (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178PubMedGoogle Scholar
  127. 127.
    Streit WJ (2004) Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 77:1–8. doi: 10.1002/jnr.20093 PubMedGoogle Scholar
  128. 128.
    Takahashi K, Prinz M, Stagi M et al (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4:e124. doi: 10.1371/journal.pmed PubMedCentralPubMedGoogle Scholar
  129. 129.
    Tamoutounour S, Guilliams M, Montanana Sanchis F et al (2013) Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39:925–938. doi: 10.1016/j.immuni.2013.10.004 PubMedGoogle Scholar
  130. 130.
    Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527. doi: 10.1371/journal.pbio.1000527.g005 PubMedCentralPubMedGoogle Scholar
  131. 131.
    Tremblay ME, Stevens B, Sierra A et al (2011) The role of microglia in the healthy brain. J Neurosci 31:16064–16069. doi: 10.1523/JNEUROSCI.4158-11.2011 PubMedGoogle Scholar
  132. 132.
    Turnbull IR, Gilfillan S, Cella M et al (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177:3520–3524PubMedGoogle Scholar
  133. 133.
    Ueno M, Fujita Y, Tanaka T et al (2013) Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16:543–551. doi: 10.1038/nn.3358 PubMedGoogle Scholar
  134. 134.
    Unger ER, Sung JH, Manivel JC et al (1993) Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J Neuropathol Exp Neurol 52:460–470PubMedGoogle Scholar
  135. 135.
    Vallières L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22:486–492PubMedGoogle Scholar
  136. 136.
    Wake H, Moorhouse AJ, Jinno S et al (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980. doi: 10.1523/JNEUROSCI.4363-08.2009 PubMedGoogle Scholar
  137. 137.
    Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013) Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci 36:209–217. doi: 10.1016/j.tins.2012.11.007 PubMedGoogle Scholar
  138. 138.
    Wang Y, Szretter KJ, Vermi W et al (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13:753–760. doi: 10.1038/ni.2360 PubMedCentralPubMedGoogle Scholar
  139. 139.
    Wohleb ES, Powell ND, Godbout JP, Sheridan JF (2013) Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci 33:13820–13833. doi: 10.1523/JNEUROSCI.1671-13.2013 PubMedCentralPubMedGoogle Scholar
  140. 140.
    Wolf Y, Yona S, Kim K-W, Jung S (2013) Microglia, seen from the CX3CR1 angle. Front Cell Neurosci 7:26. doi: 10.3389/fncel.2013.00026 PubMedCentralPubMedGoogle Scholar
  141. 141.
    Yona S, Kim K-W, Wolf Y et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38:79–91. doi: 10.1016/j.immuni.2012.12.001 PubMedCentralPubMedGoogle Scholar
  142. 142.
    Zigmond E, Varol C, Farache J et al (2012) Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37:1076–1090. doi: 10.1016/j.immuni.2012.08.026 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Institute of NeuropathologyUniversity of FreiburgFreiburgGermany
  2. 2.BIOSS Centre for Biological Signalling StudiesUniversity of FreiburgFreiburgGermany
  3. 3.Department of ImmunologyThe Weizmann Institute of ScienceRehovotIsrael

Personalised recommendations